Iontophoretic device incorporating an electrotransport adhesive

ABSTRACT

A two phase adhesive matrix for use in an electrically powered iontophoretic delivery device is provided. The adhesive matrix comprises an adhesive hydrophobic polymer phase and about 15 to 60 wt. % on a dry weight basis of a hydrophilic polymer phase distributed through the hydrophobic polymer phase. The hydrophilic phase forms upon hydration an interconnecting network of aqueous pathways for passage of the agent through the adhesive. The adhesive can be used to adhere an electrode assembly of an iontophoretic delivery device to a body surface such as skin or a mucosal membrane. Alternatively, the adhesive can be used to adhere together two or more elements of an iontophoretic delivery device.

This application is a division of application Ser. No. 07/741,475 filedAug. 6, 1991, now U.S. Pat. No. 5,240,995 which in turn is acontinuation-in-part of application Ser. No. 07/308,716 filed Feb. 9,1989, now U.S. Pat. No. 5,234,992.

TECHNICAL FIELD

This invention relates to adhesive compositions. More particularly, thisinvention relates to adhesives for use as in-line contact adhesives foriontophoretic agent delivery devices. Still more particularly, butwithout limitation thereto, this invention relates to adhesives whichpermit the passage therethrough of therapeutic agents and electrolytes,especially water soluble and ionized agents and electrolytes.

BACKGROUND ART

Iontophoresis, according to Dorland's Illustrated Medical Dictionary, isdefined to be "the introduction, by means of electric current, of ionsof soluble salts into the tissues of the body for therapeutic purposes."Iontophoretic devices have been known since the early 1900's. Britishpatent specification No. 410,009 (1934) describes an iontophoreticdevice which overcame one of the disadvantages of such early devicesknown to the art at that time, namely the requirement of a special lowtension (low voltage) source of current which meant that the patientneeded to be immobilized near such source. The device of that Britishspecification was made by forming a galvanic cell from the electrodesand the material containing the medicament or drug to be deliveredtransdermally. The galvanic cell produced the current necessary foriontophoretically delivering the medicament. This ambulatory device thuspermitted iontophoretic drug delivery with substantially lessinterference with the patient's daily activities.

More recently, a number of United States patents have issued in theiontophoresis field, indicating a renewed interest in this mode of drugdelivery. For example, U.S. Pat. No. 3,991,755 issued to Vernon et al;U.S. Pat. No. 4,141,359 issued to Jacobsen et al; U.S. Pat. No.4,398,545 issued to Wilson; and U.S. Pat. No. 4,250,878 issued toJacobsen disclose examples of iontophoretic devices and someapplications thereof. The iontophoresis process has been found to beuseful in the transdermal administration of medicaments or drugsincluding lidocaine hydrochloride, hydrocortisone, fluoride, penicillin,dexamethasone sodium phosphate, insulin and many other drugs. Perhapsthe most common use of iontophoresis is in diagnosing cystic fibrosis bydelivering pilocarpine salts iontophoretically. The pilocarpinestimulates sweat production; the sweat is collected and analyzed for itschloride content to detect the presence of the disease.

In presently known iontophoretic devices, at least two electrodes areused. Both of these electrodes are disposed so as to be in intimateelectrical contact with some portion of the skin of the body. Oneelectrode, called the active or donor electrode, is the electrode fromwhich the ionic substance, medicament, drug precursor or drug isdelivered into the body by iontophoresis. The other electrode, calledthe counter or return electrode, serves to close the electrical circuitthrough the body. In conjunction with the patient's skin contacted bythe electrodes, the circuit is completed by connection of the electrodesto a source of electrical energy, e.g., a battery. For example, if theionic substance to be delivered into the body is positively charged(i.e., a cation), then the anode will be the active electrode and thecathode will serve to complete the circuit. If the ionic substance to bedelivered is negatively charged (i.e., an anion), then the cathode willbe the active electrode and the anode will be the counter electrode.

Alternatively, both the anode and cathode may be used to deliver drugsof opposite charge into the body. In such a case, both electrodes areconsidered to be active or donor electrodes. For example, the anode candeliver a positively charged ionic substance into the body while thecathode can deliver a negatively charged ionic substance into the body.

It is also known that iontophoretic delivery devices can be used todeliver an uncharged drug or agent into the body. This is accomplishedby a process called electroosmosis. Electroosmosis is the volume flow ofa liquid (e.g., a liquid containing the uncharged drug or agent) throughthe skin induced by the presence of an electric field imposed across theskin.

Furthermore, existing iontophoresis devices generally require areservoir or source of the beneficial agent (which is preferably anionized or ionizable agent or a precursor of such agent) to beiontophoretically delivered or introduced into the body. Examples ofsuch reservoirs or sources of ionized or ionizable agents include apouch as described in the previously mentioned Jacobsen U.S. Pat. No.4,250,878, or a pre-formed gel body as described in Webster U.S. Pat.No. 4,382,529 and Ariura et al. U.S. Pat. No. 4,474,570, which patentsare incorporated herein by reference. Such drug reservoirs areelectrically connected to the anode or the cathode of an iontophoresisdevice, or optionally to an electrolyte reservoir or an ion selectivemembrane, to provide a fixed or renewable source of one or more desiredagents. See for example Parsi U.S. Pat. No. 4,731,049, incorporatedherein by reference.

It is desirable to minimize the internal electrical resistance of aniontophoretic delivery device since this allows the device to be poweredby a lower voltage, and therefore, less expensive, power source. One wayof minimizing the internal electrical resistance of the device is toestablish good electrical contact between the various components (e.g.,the electrode, the drug reservoir, any electrolyte reservoir and anyselectively permeable membrane) of the device as well as to establishgood electrical contact between the device and the body surface (e.g.,the skin or a mucosal membrane) through which the drug is to bedelivered. Along with establishing an interface for ionic and/or watersoluble species to diffuse, intimate contact between the deliverysurface of the device and the body also ensures uniform electricalcurrent distribution, thereby avoiding high localized current densitieswhich could cause damage to body tissue.

Important criteria for adhesive compositions utilized as in-line contactadhesives for iontophoretic delivery devices in general, are: sufficientadhesion allowing prolonged adhesion to a body surface and allowing easyremoval from the body surface without damaging the tissue, cohesion,bio- and chemical-compatibility, rapid drug transportability, andmechanical flexibility. When drugs are administered by electrotransportmeans rather than by passive diffusion, the adhesive should exhibit lowresistance to drug transport and should contain minimal extraneous ionswhich could undesirably compete with the drug for delivery into thebody.

The use of electrically-conductive adhesives in electrodes is known inthe art. See U.S. Pat. No. 4,008,721, (vinyl acrylic copolymer which isactivated by acetone or a low molecular weight alcohol); U.S. Pat. No.4,391,278; (polymerized 2-acrylamido-2-methylpropanesulfonic acid); U.S.Pat. No. 4,274,420; (karaya gum having an ionizable salt or a finelypowdered metal dispersed therethrough); and U.S. Pat. No. 4,566,762(cross-linked latex polymers containing an electrically conductiveaqueous phase). While these adhesives are suitable for conductingcurrent, they are not well suited for allowing agent or electrolyte(e.g., drug ions and/or electrolyte ions) to be transportedtherethrough. In addition, the solvent used in the adhesive may reactadversely with the drug or hinder the delivery of drug to the body, orconstituents incorporated in the adhesive may interfere with or competewith the agent or electrolyte for transport into the body.

Others have attempted to use self-adhering matrices comprised of a gelformed from a hydrophilic natural or synthetic material such as anatural resinous polysaccharide, plasticized with water and/or polyols.See U.S. Pat. Nos. 4,474,570 and 4,706,680.

This invention therefore provides an adhesive formulation whichovercomes many of the disadvantages associated with state of the artadhesives and is particularly suited for use as an in-line contactadhesive used to (1) adhere an iontophoretic delivery device to a bodysurface such as skin or a mucosal membrane and/or (2) to adhere togethertwo or more elements of an iontophoretic delivery device electrodeassembly, through which elements drug and/or electrolyte ions musttravel.

It is an object of this invention to provide an adhesive formulationsuitable for use as an in-line contact adhesive for electricallyassisted drug delivery systems.

It is a further object of this invention to provide an adhesive whichhas an acceptably low resistance to ionic transport when in a hydratedstate.

It is a still further object of this invention to provide such anadhesive having uniform charge distribution properties.

DISCLOSURE OF THE INVENTION

These and other objects, features and advantages are met by anagent/electrolyte-conducting adhesive for use in an iontophoreticdelivery device adapted to iontophoretically deliver an agent,preferably in the form of agent ions, through a body surface such asintact skin or a mucosal membrane. The adhesive is a two phase matrixcomprised of an adhesive hydrophobic polymer phase and about 15 to 60wt. % on a dry weight basis of a hydrophilic polymer phase distributedthrough the hydrophobic polymer phase so as to form an interconnectingnetwork of the hydrophilic polymer throughout the matrix. Theinterconnecting hydrophilic polymer network provides aqueous pathwaysfor passage of the agent or electrolyte through the matrix.

Also provided is an electrically powered iontophoretic agent deliverydevice adapted to iontophoretically deliver an agent, such as a drug,through a body surface such as intact skin or a mucosal membrane. Thedelivery device includes a donor electrode assembly, a counter electrodeassembly and a source of electrical power adapted to be electricallyconnected to the donor electrode assembly and the counter electrodeassembly. The donor electrode assembly includes an agent reservoircontaining the agent to be delivered. The agent reservoir is adapted tobe placed in agent transmitting relation with a body surface. The donorelectrode assembly also includes a donor electrode adapted to beelectrically connected to the source of electrical power. The donorelectrode is also in electrical contact with the agent reservoir.

According to one embodiment, the agent-conducting adhesive is disposedbetween the donor electrode assembly and the body surface in order toadhere the electrode assembly to the body surface. In an alternativeembodiment, the adhesive is used to adhere the agent reservoir to thedonor electrode and/or to another component in the donor electrodeassembly such as an electrolyte reservoir or a membrane. In either case,the adhesive is a two phase matrix comprised of an adhesive hydrophobicpolymer phase and about 15 to 60 wt. % on a dry weight basis of ahydrophilic polymer phase distributed through the hydrophobic polymerphase so as to form an interconnecting network of the hydrophilicpolymer throughout the matrix.

Preferably, the iontophoretic agent delivery device includes a counterelectrode assembly having an electrolyte reservoir and a counterelectrode in electrical contact with one another. The electrolytereservoir in the counter electrode assembly is adapted to be placed inelectrolyte transmitting relation with the body surface spaced apartfrom the donor electrode assembly. The electrolyte-conducting adhesiveis disposed between the electrolyte reservoir and the body surface. Theadhesive may also be used to adhere the electrolyte reservoir to thecounter electrode and/or to another component in the counter electrodeassembly such as a second reservoir or a membrane.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph presenting the electrically assisted flux ofmetoclopramide through several adhesive formulations of this invention,while the formulations are adhered to skin; and

FIG. 2 is a schematic view of an iontophoretic delivery device.

MODES FOR CARRYING OUT THE INVENTION

As used herein, the terms "iontophoresis," "electrotransport" and"electrically assisted transport" are used interchangeably and aredefined as the mechanism by which drugs are transported through a bodysurface under the influence of an electrical field. The term "bodysurface" as used herein, is defined as including without limitation,skin, body tissues, mucosal membranes, nails and blood vessel walls. Asused herein, the expressions "agent" and "drug" are used interchangeablyand are intended to have their broadest interpretation as anytherapeutically active substance which is delivered to a living organismto produce a desired, usually beneficial effect.

FIG. 2 shows one example of an electrically powered iontophoretic agentdelivery device which utilizes the adhesive of the present invention.Device 20 is adapted to iontophoretically deliver an agent, such as adrug, through a body surface such as intact skin or a mucosal membrane.The delivery device 20 includes a donor electrode assembly 18 and acounter electrode assembly 19. Electrode assemblies 18 and 19 areseparated from one another by an electrical insulator 26. Device 20 hasa top layer 21 which contains a source of electrical power (e.g., abattery) adapted to be electrically connected to the donor electrodeassembly 18 and the counter electrode assembly 19. The donor electrodeassembly 18 includes an agent reservoir 24 containing the agent to bedelivered. The agent reservoir 24 is adapted to be placed in agenttransmitting relation with a body surface. The donor electrode assembly18 also includes a donor electrode 22 adapted to be electricallyconnected to the source of electrical power. The donor electrode 22 isalso in electrical contact with the agent reservoir 24.

According to one embodiment, the agent-conducting adhesive 27 isdisposed between the donor electrode assembly 18 and the body surface inorder to adhere the electrode assembly 18 to the body surface. In analternative embodiment, the adhesive 37 is used to adhere the agentreservoir 24 to the donor electrode 22 and/or to another component inthe donor electrode assembly 18 such as an electrolyte reservoir or amembrane (both not shown in FIG. 2).

Iontophoretic agent delivery device 20 includes a counter electrodeassembly 19 having an electrolyte reservoir 25 and a counter electrode23 in electrical contact with one another. The electrolyte reservoir 25in the counter electrode assembly 19 is adapted to be placed inelectrolyte transmitting relation with the body surface spaced apartfrom the donor electrode assembly 18. The electrolyte-conductingadhesive 28 is disposed between the electrolyte reservoir 25 and thebody surface. In an alternative embodiment, the adhesive 38 is used toadhere the electrolyte reservoir 25 to the counter electrode 23 and/orto another component in the counter electrode assembly 19, such as asecond reservoir or a membrane (both not shown in FIG. 2).

The device 20 also includes a strippable release liner 29 which isremoved just prior to applying the device to a patient's body surface,e.g., skin.

This invention is an agent-conducting and electrolyte-conductingadhesive. The adhesive is a two phase matrix comprised of an adhesivehydrophobic polymer phase and a hydrophilic polymer phase which whenhydrated provide an aqueous network for passage of agent/electrolytethrough the adhesive matrix. The hydrophilic polymer phase is watersorbable and preferably non-ionic. The hydrophilic polymer phase can beeither water soluble or water insoluble. The hydrophilic polymer phasefunctions as a hydroattractant material, forming aqueous pathways in theadhesive hydrophobic polymer matrix, through which the agent andelectrolyte ions can pass through the adhesive.

The adhesive can be either in a dry or a hydrated state when applied tothe body surface, depending upon the delivery profile desired ordepending upon the stability of the other constituents, for example thedrug or electrodes, when water is present. Utilizing the adhesive in ahydrated state may facilitate the onset of drug delivery as the pathwaysfor drug/electrolyte passage will be immediately available. Hydratingthe adhesive can be accomplished in several ways. The adhesive can behydrated before packaging or it can be hydrated immediately prior toplacement on the body surface. Alternately the aqueous source can beincorporated into the electrotransport drug delivery system with abarrier separating the source from the adhesive, said barrier beingbroken or removed immediately prior to use so as to hydrate theadhesive.

It may further be desirable to place a set amount of the agent to bedelivered in the adhesive itself to provide a priming dose of agent whenthe system is placed on the body surface. Alternately, the adhesiveitself may be the drug reservoir to form a self adhering drug reservoir.To function as a reservoir, the adhesive must contain agent in an amountsufficient to maintain therapeutic delivery for an extended period oftime. The adhesive may also have other additives present such as arecommonly known in the art. These include, plasticizers which may modifythe tack and cohesive strength of the adhesive, fillers which may reducethe cost and improve handling, and antioxidants which improve theresistance of the adhesive to oxidative degradation.

Blending of the hydrophobic and hydrophilic polymer components is donemechanically, either in solution or by milling, extrusion or hot meltmixing, for example. The resulting adhesive films may then be preparedby solvent casting, extrusion or by melt processing, for example.

State of the art adhesives which are comprised of hydrophobic polymers,normally are only capable of absorbing less than 2% of their own weightin water. The presence of water and the resulting aqueous pathways iscritical to the success of this invention and the addition of thehydrophilic polymer phase to the hydrophobic polymer creates an adhesivewhich is capable of absorbing water within the range of about 7 to 80%of the total adhesive weight.

The hydrophilic polymer phase can be present within the range of about15 to 60 wt. % on a dry weight basis, with the preferred range beingabout 30 to 40 wt. % on a dry weight basis. The hydrophobic polymerphase comprises about 40 to 85 wt. % on a dry weight basis, andpreferably about 60 to 70 wt. % on a dry weight basis, of the adhesivematrix. A suitable amount of hydrophilic polymer is that which providesan interconnecting network of the hydrophilic polymer throughout thematrix, generally at least about 15 wt. % hydrophilic polymer. On theother hand, the amount of the hydrophilic polymer should not be so greatthat it significantly lowers the adhesive strength of the adhesive,generally no more than about 60 wt. %. Keeping this criteria in mind,increasing the amount of hydrophilic polymer within this range willincrease the current distribution but will also decrease the adhesivestrength.

Preferably, the hydrophilic polymer is mixed with the hydrophobicpolymer in the form of hydrophilic polymer particles. The averageparticle size can be up to about 180 μm. The particle size selected ispreferably related to the thickness of the adhesive. For a 5 mil thickadhesive, the average particle size should be no larger than about 125μm. For 2-3 mil thick adhesives, the preferred particle size is lessthan about 40 μm.

The hydrophobic polymer itself can have adequate adhesive properties orit may be rendered adhesive by the addition of tackifying resins.

Suitable hydrophobic polymers include, without limitation, acrylic ormethacrylic resins such as polymers of esters of acrylic or methacrylicacid with alcohols such as n-butanol, n-pentanol, isopentanol, 2-methylbutanol, 1-methyl butanol, 1-methyl pentanol, 2-methyl pentanol,3-methyl pentanol, 2-ethyl butanol, isooctanol, n-decanol, orn-dodecanol, alone or copolymerized with ethylenically unsaturatedmonomers such as acrylic acid, methacrylic acid, acrylamide,methacrylamide, N-alkoxymethyl acrylamides, N-alkoxymethylmethacrylamides, N-tert-butylacrylamide, itaconic acid, ethylenevinylacetate copolymers, N-branched alkyl maleamic acids wherein thealkyl group had 10-24 carbon atoms, glycol diacrylates, or mixtures ofthese. Typical examples of commercially available acrylate adhesivessuitable for use in this invention are the polyvinylacetate compoundssold by Monsanto Polymer Products Co. under the name of GELVA, such asGELVA 737 and GELVA 788, acrylate adhesives sold by the 3M Company suchas 3M #9871 and 3M #9872, and sold by The Kendall Company under the nameKendall A200C-0. Also suitable are silicone adhesives which are preparedby the reaction of a linear polydimethylsiloxane fluid with asolvent-soluble, low molecular weight silicate resin. A typical exampleof a silicone adhesive suitable for use in this invention is a medicalgrade silicone pressure-sensitive adhesive commercially available underthe trademark DOW CORNING®355 Medical Grade Adhesive from Dow CorningCorporation. Plasticizers may also be added. A preferred plasticizer forsilicone adhesives is silicone medical fluid.

Suitable hydrophobic polymers which can be rendered adhesive by theaddition of tackifying resins include, without limitation,poly(styrene-butadiene) and poly(styrene-isoprene-styrene) blockcopolymers, ethylene vinyl acetate polymers such as those which aredescribed in U.S. Pat. No. 4,144,317, plasticized or unplasticizedpolyvinylchloride, natural or synthetic rubbers, C₂ -C₄ polyolefins suchas polyethylene, polyisoprene, polyisobutylene and polybutadiene.Examples of suitable tackifying resins include, without limitation,fully hydrogenated aromatic hydrocarbon resins, hydrogenated esters andlow molecular weight grades of polyisobutylene. Particularly suitableare tackifiers sold under the trademarks Staybelite Ester® #5 and #10Regal-Rez® and Piccotac®, by Hercules, Inc. of Wilmington, Del.

Suitable hydrophilic polymers include, without limitation,polyacrylamide (hereinafter "PAA"), Klucel®, cross-linked dextran suchas Sephadex (Pharmacia Fine Chemicals, AB, Uppsala, Sweden),polyvinylalcohol (hereinafter "PVA"), WaterLock (Grain Processing Corp.,Muscatine, Iowa) which is a starch-graft-poly(sodiumacrylate-co-acrylamide) polymer, cellulosic derivatives such ashydroxypropylmethylcellulose (hereinafter "HPMC"), low- substitutedhydroxypropylcellulose (hereinafter "LHPC") and cross-linkedNa-carboxymethylcellulose such as Ac-Di-Sol (FMC Corp., Philadelphia,Pa.), hydrogels such as polyhydroxyethyl methacrylate (hereinafter"pHEMA") (National Patent Development Corp.), blends of polyoxyethyleneor polyethylene glycols with polyacrylic acid such as Polyox® blendedwith Carbopol®, cross-linked polyvinyl pyrrolidone (hereinafter "PVP")(GAF Corporation), natural gums and chitosan. Also suitable arephospholipids such as L-α-phosphatidylcholine (Sigma Chemical Company).

The two phase adhesive matrix according to this invention hashydrophilic pathways in order to allow agent and/or electrolyte (e.g.,agent or electrolyte ions) to pass through the adhesive under theinfluence of an electric field, i.e., the adhesive presents minimal masstransport resistance. The adhesive also has good hydration kinetics sothat the time it takes to absorb water (e.g., from the body) and beginpassing current, is acceptable. A suitable time to reach steady statemoisture content is less than about 5 hours preferably less than 1 hour,most preferably less than 10 minutes. Further, the adhesive layerprovides for uniform current distribution so as to avoid highlylocalized current densities which could result in tissue damage.

The adhesive of the present invention exhibits excellent ionicconductivity so it is not rate limiting and does not require significantvoltage during system operation, i.e., the adhesive presents minimalelectrical resistance. State of the art adhesives have been shown to beessentially blocking to ionic transport in that ions are unable to passthrough the adhesive. By incorporating the hydrophilic polymer phase,the adhesive of this invention has been shown to exhibit an arearesistance of less than about 10 kohm-cm², preferably less than about 5kohm-cm², most preferably less than about 1 kohm-cm² for a typical 3 milthick sample, or most preferably less than about 0.33 kohm-cm² per milthickness of adhesive.

Having thus generally described our invention, the following exampleswill illustrate how variations of the above described parameters provideadhesives suitable for use as in-line contact adhesives forelectrotransport systems.

EXAMPLE I

Several acrylate-based adhesive formulations were tested in vitro toevaluate the electrically assisted and passive transport of the drugmetoclopramide. Adhesive samples 5 mils in thickness were laminated ontoflexible polyester cloth for support and mounted into cells designed forelectrotransport permeation experiments. The sample side having exposedadhesive was positioned toward the anode. An aqueous donor solutioncontaining 0.1 g/ml metoclopramide HCl was placed on the anode side ofthe cell. The receptor solution was Dulbecco's phosphate buffered salineat pH 7 and a total salt concentration of about 0.15M (hereinafter"DPBS"). Experiments were conducted at 32° C. for 5 hours.Metoclopramide transport across the adhesive/cloth laminate wasmeasured, both with and without 0.1 mA/cm² of applied electricalcurrent. The receptor solution was sampled and the cell voltage acrossthe films was monitored every hour. The hydrophobic polymer used wasKendall A200C-0, an acrylate adhesive. The hydrophilic polymer waspHEMA, in the form of particles loaded in 20, 30, and 40 weight percent(wt. %) amounts. The average particle size was within the range of74-177 μm. Both electrically assisted and passive transport ofmetoclopramide through the Kendall A200C-0/pHEMA adhesives was high,exceeding 1 mg/cm² -hr, thus establishing that the adhesives presentedminimal mass transport resistance.

EXAMPLE II

Several adhesive films according to this invention were solvent cast andtested in vitro (32° C.) to measure the cell potential duringelectrically assisted transport of metoclopramide. The aqueous donorsolution contained 0.1 g/ml metoclopramide and the receptor solution wasDPBS. The cells had an anodic polarity and were run at a current of 0.1mA/cm². The films tested were comprised of 70 wt. % hydrophobic polymerand 30 wt. % hydrophilic polymers. The hydrophobic polymers tested weresilicone adhesive and the acrylate adhesives GELVA 788 and GELVA 737.The hydrophilic polymers tested was LHPC, in the form of particleshaving an average particle size of less than 63 μm. Control adhesivefilms comprised solely of hydrophobic polymer were also tested. Thepotentials across each cell and the equivalent resistances are presentedin the following table:

                  TABLE I                                                         ______________________________________                                                                    Specific                                                            Area      Resistance                                                 Potential                                                                              Resistance                                                                              (kohm-cm.sup.2 /                                                                       Thickness                                Adhesive (volts)  (kohm-cm.sup.2)                                                                         mil)     (mils)                                   ______________________________________                                        Silicone 0.084    0.84      0.28     3                                        Adhesive/                                                                     LHPC                                                                          GELVA 788/                                                                             0.024    0.24      0.10     2.5                                      LHPC                                                                          GELVA 737/                                                                             0.016    0.16      0.05     3                                        LHPC                                                                          Silicone >30      >200      >100     2                                        Adhesive                                                                      GELVA 788                                                                              4.6      46        18       2.5                                      GELVA 737                                                                              3        30        20       1.5                                      ______________________________________                                    

As shown in Table I, the two phase adhesive matrices comprised of 30 wt.% hydrophilic polymer exhibited specific resistances well within themost preferred range of less than 0.33 kohm-cm² per mil thickness ofadhesive, and therefore have low voltage requirements during use. Incomparison, the adhesive films having no hydrophilic additive exhibitedarea resistances at least 2 orders of magnitude higher than those of thepresent invention.

EXAMPLE III

Several adhesive films having an approximate thickness of 3 mils weremade according to this invention, having a composition of 70 wt. %hydrophobic polymer (silicone adhesive, GELVA 788 and GELVA 737) and 30wt. % hydrophilic polymer (PVA, particles having an average particlesize of <63 μm). These adhesives were solvent cast, adhered to humancadaver skin and tested as in Example II. Two samples of each adhesivewere run using eight skin samples from the same donor. The electricallyassisted flux using 0.1 mA/cm² (averaged for the two samples) formetoclopramide versus time is plotted in the Figure and the voltagesacross each cell are presented in the following table:

                  TABLE II                                                        ______________________________________                                                           Cell Voltage (volts)                                       Adhesive             Sample 1 Sample 2                                        ______________________________________                                        Skin only            1.59     0.83                                            Skin + Silicone Adhesive/PVA                                                                       0.66     0.75                                            Skin + GELVA 788/PVA 0.75     0.81                                            Skin + GELVA 737/PVA 1.20     1.50                                            ______________________________________                                    

The data in the Figure establishes that the flux across skin does notchange appreciably when the adhesive of this invention is added. This isdesirable as the adhesive should not present a significant barrier tomass transport. The data in Table II also indicates that the voltageacross the skin only has a fairly broad variability between differentskin samples (0.83 to 1.59 volts). However, within this range the datashows that the cell voltage does not significantly increase when theadhesive of this invention is placed on the skin. Therefore, theadhesive itself appears to have a much lower electrical resistance thanthe resistance of the skin alone.

EXAMPLE IV

The acrylate-based adhesives of Example I were also tested as to theirelectrical resistance. The resistance of the Kendall A200C-0/pHEMAadhesives were on the order of 1 kohm-cm². The electrical resistance ofthe Kendall A200C-0 acrylate adhesive without any pHEMA added wasapproximately 15 kohm-cm².

EXAMPLE V

Several adhesive film compositions were evaluated for currentdistribution characteristics. The hydrophobic polymers used weresilicone adhesive alone, silicone adhesive with silicone medical fluidand the acrylate adhesives GELVA 788 and GELVA 737. The hydrophilicpolymers were either LHPC or PVA particles, having an average particlesize of less than 63 μm. The adhesives were directly cast in thicknessesof approximately 3 mils onto copper foil and mounted as the anode in anelectrochemical cell. The cathode was Ag/AgCl and the electrolytesolution was 0.1M copper sulfate/0.5M sulfuric acid/0.01M sodiumchloride solution. The test was run at room temperature for 6 hours at acurrent density of 0.5 mA/cm². As current flows, copper metal isoxidized underneath the adhesive film. At the conclusion of theexperiment, the adhesive was dissolved from the copper foil and thesurface of the foil inspected for uniformity of copper dissolution. Thefollowing data was obtained where hydration time was the time to reach75% of the steady state voltage.

                                      TABLE III                                   __________________________________________________________________________    Weight Percent              Hydration                                                                           Avg. Steady                                 Silicone                                                                           Silicone                                                                            GELVA                                                                              GELVA       Time  State Cell                                  Adhesive                                                                           Med. fluid                                                                          788  737  LHPC                                                                              PVA                                                                              (hours)                                                                             Voltage (volts)                             __________________________________________________________________________    80                   20     <3.1  0.22                                        70                   30     <1    0.123                                                  70        30     <0.25 0.202                                                       70   30     <0.25 0.2                                                    60        40     <0.1  0.13                                                        60   40     <0.25 0.11                                        67.5 2.5             30     <1.6  0.18                                        57.5 2.5             40     <1    0.1                                         55   5               40     <1    0.11                                        80                       20 <0.5  0.31                                        70                       30 <0.25 0.15                                                   70            30 <0.25 0.12                                                        70       30 <0.5  0.48                                        67.5 2.5                 30 <0.5  0.14                                        __________________________________________________________________________

While lower voltages are preferable, this is not always an indication ofa better adhesive film since a low voltage (or low adhesive resistance)may be due to the presence of isolated defects in the adhesive, whereall the current could pass through a small area rather than beinguniformly distributed over the entire surface of the adhesive. Thesilicone adhesive formulations exhibited lower overall steady statevoltages but showed spots of high current density. The acrylateadhesives showed a more uniform current distribution pattern and shorterhydration times, with the steady state voltages of GELVA 788 beingsomewhat greater than those of GELVA 737.

EXAMPLE VI

Electrochemical dissolution of a metal in intimate contact with apolymeric film occurs at the hydrated hydrophilic polymer pathways.Therefore, the electrical current distribution across an adhesive isrevealed by observing the dissolution pattern created on a metal foilcovered or coated by an adhesive. An 80 wt. % Kendall A200C-0/20 wt. %pHEMA particles (average particle size within the range of 74-177 μm)adhesive film was cast onto copper foil (0.0025 mm thick) to a driedfilm thickness of 5 mils. The copper/adhesive laminate was then mountedas the anode in an electrochemical cell. The cathode was Ag/AgCl and a0.5M sulfuric acid/0.01M sodium chloride solution was used as theelectrolyte solution. Triplicate samples of copper/adhesive wereevaluated for 1, 4, 8 and 24 hours using a current of 0.1 mA/cm². Anuncoated copper foil was also included for each set of samples.Following dissolution, the samples were rinsed with water, the adhesivelayer was dissolved using methylene chloride, and the dissolutionpattern on the copper surface was observed. Between 1 and 8 hours, noholes had formed on the coated sample, but the surface showed scatteredminute dark spots, no larger than the diameter of a pin, which probablyconsisted of copper oxide. In contrast, the uncoated sample wasuniformly discolored. After 24 hours, randomly dispersed holes (pinholesize or smaller) were observed on the coated sample. After 24 hours,discoloration of the uncoated sample was uniform, but darker than at 8hours. Comparison of the dissolution patterns of the adhesive coated anduncoated foil samples indicated that the electrical current distributionacross the adhesive was adequately distributed across the surface asevidenced by the random dispersion of pits and holes. Increasing theloading of pHEMA and decreasing the particle size improves the currentdistribution since increased pHEMA loadings increase the density ofhydrated hydrophilic polymer pathways per unit area.

EXAMPLE VII

Several acrylate-based adhesive formulations were tested as to tack or"stickiness". Kendall A200C-0 was loaded with 20, 30 and 40 wt. % pHEMAparticles (average particle size within the range of 74-177μ). All threefilms were tacky. Tack was highest for the film with 20 wt. % pHEMA andlowest for the film with 40 wt. % pHEMA. Additionally, silicone basedadhesives containing various levels of pHEMA and acrylate adhesives(e.g., GELVA 788 and GELVA 737) containing various levels of pHEMA werecompared. All formulations tested exhibited sufficient tack andelasticity for use in an electrotransport transdermal system.

EXAMPLE VIII

Prolonged adhesion to the skin was evaluated using 1/2" diameter patchescomposed of 70 wt. % Kendall A200C-0/30 wt. % pHEMA particles (averageparticle size within the range of 74-177 μm) films laminated to flexiblepolyester cloth backing (non-occlusive) and to ethylene vinylacetatecoated polyester film (occlusive). These patches were worn on the arm byseveral subjects. After 7 hours, the patches were still adhering to theskin. No difference in wearability was observed regardless of whichbacking material was used.

EXAMPLE IX

Several adhesive formulations according to this invention were solventcast as approximately 3 mil thick films having a disc area of 11.4 cm².The total water uptake was then evaluated by placing the formulations ina glass desiccator chamber, preheated to 32° C., containing a saturatedsolution of Na₂ HPO₄. 7H₂ O which produced a 95% relative humidityatmosphere. Water uptake was measured by the total water absorbed (% drybasis). The adhesive compositions tested were comprised of 70 wt. %hydrophobic polymer and 30 wt. % hydrophilic polymer in the form ofparticles having an average particle size of <63μ. The hydrophilicpolymers tested were LHPC (equilibrium moisture content=20.5% at 95%relative humidity), PVA (equilibrium moisture content=34.5% at 95%relative humidity) and PAA. The hydrophobic polymers tested weresilicone adhesive, GELVA 788 and GELVA 737.

                  TABLE IV                                                        ______________________________________                                        Hydro-            Total Water Absorbed                                        philic Hydrophobic                                                                              Time,   % of                                                Polymer                                                                              Polymer    hrs     particle wt                                                                           % of adhesive wt                            ______________________________________                                        --     Sil. Adhesive                                                                            8       0       0                                                  GELVA 788  8       0       0                                                  GELVA 737  8       0       0                                           LHPC   Sil. Adhesive                                                                            8.5     12.5    3.8                                                GELVA 788  8.5     23.0    6.9                                                GELVA 737  8.5     19.5    5.3                                         PVA    Sil. Adhesive                                                                            8.2     21.0    6.3                                                GELVA 788  8.2     20.5    6.2                                                GELVA 737  8.2     19.5    5.9                                         PAA    Sil. Adhesive                                                                            8.2     51      15.3                                               GELVA 788  8.2     60      18.0                                               GELVA 737  8.2     59      17.7                                        ______________________________________                                    

EXAMPLE X

A solid drug reservoir composed of 50 wt. %hydroxypropylmethyl-cellulose and 50 wt. % metoclopramide HCl wassolvent cast from an aqueous solution to form a film. After drying, a 1"diameter disk of the film was laminated between a 1" disk of silver foiland a 1" disk of the adhesive being tested. One control system was madecomprised of only the metoclopramide-containing film and silver foil.The control system had no adhesive layer.

The adhesives were made by solvent casting from a freon solution. Eachadhesive contained 68 wt. % hydrophobic polymer matrix (Dow CorningX7-2920 silicone adhesive), 2 wt. % of a resinous tackifying agent(silicone medical fluid) and 30 wt. % of hydrophilic polymer particles.

After lamination, the systems were hydrated in a 95% relative humidityenvironment for 2 hours and 15 minutes. Following hydration, a 1" diskof heat stripped human cadaver epidermis was placed with the stratumcorneum side facing the exposed adhesive surface.

The three adhesive-containing systems and the adhesive-free controlsystem were then mounted in an electrotransport permeation cell having apermeation area of 1.26 cm². DPBS was used as a receptor solution. Thesilver foil was anodically polarized and the current was controlled at100 μA/cm² using a Princeton Applied Research Potentiostat/GalvanostatModel 363. The transport of metoclopramide into the receptor compartmentwas determined hourly over a period of 5 hours by measuring the UVabsorbance of the receptor solutions at 310 nanometers using a HewlettPackard Spectrophotometer Model 8452A. Steady state flux was achieved bythe 3rd hour and calculated by taking the average flux over hours 3, 4and 5. The average steady state flux of metoclopramide is given in TableV. A comparison with the control system (which had no adhesive)demonstrates that the steady state flux of metoclopramide was onlyminimally impeded by the presence of the adhesive.

                  TABLE V                                                         ______________________________________                                                                Avg. Cell Steady State                                Adhesive                                                                              Hydrophilic     Voltage   Flux                                        No.     Polymer         (volts)   (μg/cm.sup.2 -hr)                        ______________________________________                                        Control --              0.5       148                                         1       Starch-graft-poly(Na                                                                          3.4       129                                                 acrylate-co-acrylamide).sup.1                                         2       Polyvinyl pyrrolidone.sup.2                                                                   2.4       115                                         3       Polyethylene oxide.sup.3                                                                      5 5       120                                         ______________________________________                                         .sup.1 Water Lock A180 sold by Grain Processing Corp. of Muscatine, IA        .sup.2 PVPxl sold by GAF Corp.                                                .sup.3 Polyox ® sold by Union Carbide Corp.                          

Having thus generally described our invention and described in detailcertain preferred embodiments thereof, it will be readily apparent thatvarious modifications to the invention may be made by workers skilled inthe art without departing from the scope of this invention as defined bythe following claims.

What is claimed is:
 1. An electrically powered iontophoretic agentdelivery device including a donor electrode assembly, a counterelectrode assembly and a source of electrical power adapted to beelectrically connect to the donor electrode assembly and the counterelectrode assembly, the donor electrode assembly including:a) an agentreservoir containing an agent, the agent reservoir adapted to be placedin agent transmitting relation with a body surface; b) a donor electrodeadapted to be electrically connected to the source of electrical power,the donor electrode being in electrical contact with the agentreservoir; and c) a two phase adhesive disposed between the agentreservoir and the body surface for adhering the donor electrode assemblyto the body surface, the adhesive comprising an adhesive hydrophobicpolymer phase and about 15 to 60 wt. % on a dry weight basis of ahydrophilic polymer phase distributed through the hydrophobic polymerphase, the hydrophilic phase forming upon hydration an interconnectingnetwork of the hydrophilic polymer throughout the matrix, the networkproviding aqueous pathways for passage of the agent through the matrix.2. An electrically powered iontophoretic agent delivery device includinga donor electrode assembly, a counter electrode assembly and a source ofelectrical power adapted to be electrically connected to the donorelectrode assembly and the counter electrode assembly, the donorelectrode assembly including:a) an agent reservoir containing an agent,the agent reservoir adapted to be placed in agent transmitting relationwith a body surface; b) a donor electrode adapted to be electricallyconnected to the source of electrical power and the agent reservoir; andc) a two phase adhesive disposed between the agent reservoir and thedonor electrode for adhering the donor electrode to the agent reservoir,the adhesive comprising an adhesive hydrophobic polymer phase and about15 to 60 wt. % on a dry weight basis of a hydrophilic polymer phasedistributed through the hydrophobic polymer phase, the hydrophilic phaseforming upon hydration an interconnecting network of the hydrophilicpolymer throughout the matrix, the network providing aqueous pathwaysfor passage of the agent through the matrix.
 3. The device of claim 1 or2, wherein the matrix comprises about 30 to 40 wt. % on a dry weightbasis of the hydrophilic polymer.
 4. The device of claim 1 or 2, whereinthe adhesive is capable of absorbing about 7 to 80 wt. % water based onthe total weight of the adhesive.
 5. The device of claim 1 or 2, whereinthe hydrophilic polymer is selected from the group consisting ofpolyacrylamide, cross-linked dextran, polyvinylalcohol,starch-graft-poly(sodium acrylate-co-acrylamide) polymers, cellulosicderivatives, hydroxypropylmethyl cellulose, low-substitutedhydroxypropyl cellulose, cross-linked Na-carboxymethylcellulose,hydrogels, polyhydroxyethyl methacrylate, blends of polyoxyethylene andpolyethylene glycols with polyacrylic acid, polyethylene oxides andcross-linked polyvinyl pyrrolidone.
 6. The device of claim 1 or 2,wherein the hydrophilic polymer is in the form of particles having aparticle size of up to about 175 μm.
 7. The device of claim 6, whereinthe hydrophilic particles have a particle size of up to about 35 μm. 8.The device of claim 1 or 2, wherein the adhesive exhibits a specificresistance of less than about 0.33 kohm-cm² per mil thickness ofadhesive.
 9. The device of claim 1 or 2, wherein the hydrophobic polymeris selected from the group consisting of acrylate adhesives and siliconeadhesives.
 10. The device of claim 1 or 2, wherein the hydrophobicpolymer phase is rendered adhesive by adding thereto a tackifying resin.11. The device of claim 10, wherein the hydrophobic polymer is selectedfrom the group consisting of poly(styrene-isoprenestyrene) blockcopolymers, ethylene vinyl acetate polymers, plasticized andunplasticized polyvinylchloride, natural and synthetic rubbers, C₂ -C₄polyolefins, polyethylene, polyisoprene, polyisobutylene andpolybutadiene.
 12. The device of claim 10, wherein the tackifying resinis selected from the group consisting of fully hydrogenated aromatichydrocarbon resins, hydrogenated esters and low molecular weight gradesof polyisobutylene.
 13. The device of claim 1 or 2, wherein the agentcomprises a drug.
 14. The device of claim 13, wherein the drug is awater soluble drug salt.
 15. The device of claim 1 or 2, wherein theagent comprises an electrolyte.
 16. The device of claim 15, wherein theelectrolyte is a water soluble electrolyte salt.